This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obstructive sleep apnea (OSA) is a complex disorder characterized by the repeated collapse of the pharyngeal airway during sleep and is associated with snoring, frequent cortical arousals, overnight hypoxemia and daytime hypersomnolence. The major defining metric of OSA is the apnea hypopnea index (AHI) which averages the number of complete and partial airway occlusions that occur hourly during sleep. With a 9 to 24% prevalence in U.S. adults for mild-moderate cases (defined by an AHI e 5) and 2-9% for moderate cases (defined by an AHI e 15), OSA and its co-morbidities (obesity, hypertension, and diabetes) are a high public health burden. Increasing evidence suggests a genetic basis for OSA;however, it is unclear which genetic variants for OSA overlap those for obesity, a factor associated with a 4 to 10 fold increased risk of OSA. To understand the genetics of sleep apnea, we evaluated the relationship between the apnea hypopnea index (AHI) and body mass index (BMI) through linkage analysis to identify genetic loci that may influence AHI and BMI jointly and AHI independent of BMI. Haseman-Elston sibling regression was conducted on AHI, AHI adjusted for BMI and BMI in African-American and European-American pedigrees. A comparison of the magnitude of the linkage peaks was used to assess the relationship between AHI and European-American BMI. In European Americans the strongest evidence for linkage to AHI was on 6q23-25 and 10q24-q25, both decreasing after BMI adjustment, suggesting loci with pleiotropic effects. Also, a promising area of linkage to AHI but not BMI was observed on 6p11-q11 near the orexin-2 receptor, suggesting BMI independent pathways. In African-Americans the strongest evidence of linkage for AHI after adjusting for BMI was on chromosome 8p21.3 with linkage increasing after BMI adjustment and on 8q24.1 with linkage decreasing after BMI adjustment. Novel linkage peaks were also observed in African- Americans to both BMI and AHI on chromosome 13 near the serotonin-2a receptor. These analyses suggest genetic loci for sleep apnea that operate both independently of BMI and through BMI-related pathways.